GRANULOMATOUS HEPATITIS

Granulomas may be found in the liver of patients with a known systemic disease, such as tuberculosis or sarcoidosis, and in patients who are asymptomatic and whose liver function test findings are abnormal. The term granulomatous hepatitis has been used to describe patients with granulomas in the liver who have abnormal liver function or nonspecific symptoms of fever and malaise.
Recent studies on granulomatous hepatitis appear to show differences in the etiology of this disease in comparison with earlier studies. Guckian and Perry (1965) reviewed 63 cases of granulomatous hepatitis and noted many different causes, including infections (viral, bacterial, fungal, rickettsial), hypersensitivity diseases (drugs and berylliosis), and vascular and connective tissue diseases (Wegener’s granulomatosis, rheumatoid arthritis, sarcoidosis). Fifty-three percent of patients had tuberculosis, 12% had sarcoidosis, and 2% had an unknown disease. As might be expected, recent studies show a different distribution of diagnoses, with tuberculosis becoming much less common.
Sartin and Walker (1991) reviewed 88 cases of granulomatous hepatitis from the Mayo Clinic. In 50%, disease was confined to the liver, and a diagnosis of idiopathic granulomatous hepatitis was made. Twenty-two percent of patients had sarcoidosis, and only 3% had tuberculosis. Patients in whom idiopathic disease was diagnosed had a benign course.
Zoutman et al. (1991) reviewed a series of patients with fever of unknown origin who were found to have granulomatous hepatitis on liver biopsy. Of 23 patients, only 26% were given a specific diagnosis, and only two patients had mycobacterial disease. In the remaining 74% of patients, no specific diagnosis was made after 41 months of follow-up. All 17 patients had a benign course and remained well, although seven required long-term prednisone therapy.
Recent reports emphasize the wide differential for granulomatous hepatitis. Infections such as Q fever and Lyme disease may cause granulomatous hepatitis. Lenoir et al. (1988) reported three patients with cat scratch fever. The Warthin-Starry silver stain showed organisms consistent with the cat scratch bacillus. Bartonella henselae has been increasingly recognized as a cause of granulomatous hepatitis and splenitis. Granulomatous hepatitis has been reported in association with secondary syphilis. Systemic Yersinia enterocolitica infection has caused granulomatous hepatitis with acute necrosis.
Granulomatous hepatitis continues to be reported as a drug effect. Quinidine, diltiazem, hydralazine, methimazole, glyburide, paracetamol, pyrazinamide, and interferon alfa have recently been reported to cause granulomatous hepatitis. Bladder instillation of bacille Calmette-Guérin vaccine for the treatment of bladder carcinoma has also been reported to cause granulomatous hepatitis, both by hematogenous dissemination and as a hypersensitivity reaction. In one study of patients with rheumatoid arthritis receiving gold therapy, gold pigment could be demonstrated in lipogranulomas by radiographic microanalysis.
Mahida et al. (1988) described familial granulomatous hepatitis. Two West Indian parents and three of seven offspring had the disease. No cause or extrinsic etiology could be identified. Granulomatous hepatitis may be a manifestation of lymphoma, although abnormal cells will often be detected with these lesions.
Because of the many etiologies for granulomatous hepatitis, a thorough history and physical examination must direct the workup. Examination of the lung and skin and a search for lymphadenopathy will be particularly important. A detailed history should include all medications and drugs taken by the patient. A history of cough, fever, drenching sweats, and weight loss suggests tuberculosis. Chest roentgenography, determination of serum calcium level, Venereal Disease Research Laboratory (VDRL) test, urine analysis, and tuberculosis skin test will be routinely performed. Liver biopsy material should be cultured for fungi and mycobacteria. Acid-fast, hematoxylin-eosin, and methenamine silver stains should also be performed. Serology for Q fever, brucellosis, syphilis, and hepatitis are recommended. Angiotensin-converting enzyme may be indicated in patients with pulmonary disease in whom sarcoidosis is being considered.
Some patients with miliary tuberculosis may have negative results on stains for acid-fast bacilli. Clinical judgment will be needed to determine when empiric therapy for tuberculosis is indicated. Additional cultures and biopsies of bone marrow, lymph node, or lung lesions may be necessary.
When the suspicion for tuberculosis is low, corticosteroid treatment has proved useful in symptomatic patients with sarcoidosis or idiopathic granulomatous hepatitis. Methotrexate has been reported to be successful therapy in some patients with idiopathic granulomatous hepatitis. (S.L.B.)
Bibliography
Blest S, Schubert TT. Chronic Epstein-Barr virus infection: a cause of granulomatous hepatitis? J Clin Gastroenterol 1989;11:343.
Granulomatous hepatitis was found in a patient who had IgM antibody to viral capsid antigen.
Braylan RC, et al. Malignant lymphoma obscured by concomitant epithelioid granulomas. Cancer 1977;39:1146.
Nonnecrotic hepatic granulomas were associated with malignant lymphoma.
Fitzgerald MX, Fitzgerald O, Towers RP. Granulomatous hepatitis of obscure etiology. Q J Med 1971;40:371.
A discussion of selective aspects of the problem of granulomatous hepatitis, the value of the Kveim test, and the value of therapeutic trials of antituberculosis therapy.
Guckian JC, Perry JE. Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann Intern Med 1965;65:1081.
Excellent classic article and detailed discussion of etiology. Tuberculosis is no longer as common a cause of granulomatous hepatitis.
Israel HL, Goldstein RA. Hepatic granulomatosis and sarcoidosis. Ann Intern Med 1973;79:669.
Extraabdominal investigation can provide evidence that sarcoidosis is the cause of febrile hepatic granulomatosis. The Kveim reaction has little value in excluding sarcoidosis.
Knobel B, et al. Pyrazinamide-induced granulomatous hepatitis. J Clin Gastroenterol 1997;24:264.
First documented case of pyrazinamide causing granulomatous hepatitis, with clinical symptoms of hectic fever, chills, and extreme fatigue 4 weeks after pyrazinamide was begun.
Knox T, et al. Methotrexate treatment of idiopathic granulomatous hepatitis. Ann Intern Med 1995;122:592.
Patients with granulomatous hepatitis for whom no etiologic agent can be found may respond to treatment with methotrexate. Patients who have failed corticosteroid therapy have responded to methotrexate.
Landas SK, et al. Lipogranulomas and gold in the liver in rheumatoid arthritis. Am J Surg 1992;16:171.
Study of patients with severe rheumatoid arthritis on methotrexate in whom liver biopsy was performed routinely. Patients who had been on gold therapy had lipogranulomas with pigment representing gold deposition.
Lenoir AA, et al. Granulomatous hepatitis associated with cat scratch disease. Lancet 1988;21:1121.
Describes three patients with granulomatous hepatitis and cat scratch fever. Only one patient had peripheral lymphadenopathy. Results of Warthin-Starry silver stain of the liver were positive.
Liston TE, Koehler JE. Granulomatous hepatitis and necrotizing splenitis due to Bartonella henselae in a patient with cancer. Clin Infect Dis 1996;22:951.
A case report of B. henselae causing granulomatous hepatitis and necrotizing splenitis in an adult cancer patient undergoing chemotherapy. Forty-one cases of Bartonella infection of the liver and spleen are reviewed. Bartonella may cause liver disease in immunocompetent or immunosuppressed patients. Not all patients have contact with dogs or cats.
Maddrey WC, et al. Sarcoidosis and chronic hepatic disease: a clinical and pathologic study of 20 patients. Medicine (Baltimore) 1970;49:375.
A positive Kveim reaction in patients with sarcoidosis and hepatic granuloma is correlated with the presence of enlarged hilar nodes.
Mahida Y, et al. Familial granulomatous hepatitis: a hitherto unrecognized entity. Am J Gastroenterol 1988;83:42.
Parents and three offspring had granulomatous hepatitis. Granulomas were also found in muscles, lymph nodes, and pleurae.
Mathus S, Dooley J, Scheuer PJ. Quinine-induced granulomatous hepatitis and vasculitis. Br Med J 1990;300:613.
Report of quinine as cause of hepatitis and vasculitis. Quinine was also implicated in an earlier report (Br Med J 1983;286:264).
Mills P, et al. Ultrasound in the diagnosis of granulomatous liver disease. Clin Radiol 1990;41:113.
Patients with granulomatous hepatitis often have suggestive hypoechoic halos on ultrasound.
Neville E, Piyasena KHG, James DG. Granulomas of the liver. Postgrad Med J 1975; 51:361.
A review of the clinical, biochemical, and immunologic features of diseases that produce hepatic granuloma.
Port J, Leonidas JC. Granulomatous hepatitis in cat-scratch disease. Ultrasound and CT observations. Pediatr Radiol 1991;21:598.
Case of cat scratch disease and granulomatous hepatitis. Abdominal ultrasound showed multiple well-circumscribed, low-attenuation areas in the liver.
Rice D, Burdick CO. Granulomatous hepatitis from hydralazine therapy [Letter]. Arch Intern Med 1983;143:1077.
Hydralazine is reported to cause granulomatous hepatitis.
Sarachek NS, London RL, Matulewica TJ. Diltiazem and granulomatous hepatitis. Gastroenterology 1985;88:1260.
Patient on diltiazem in whom fever and liver function test abnormalities developed had biopsy-proven granulomatous hepatitis.
Sartin JS, Walker RC. Granulomatous hepatitis: a retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc 1991;66:914.
Retrospective review of 88 cases from the Mayo Clinic. Fifty percent of patients had idiopathic hepatitis. Only 3% had tuberculosis.
Saw D, et al. Granulomatous hepatitis associated with glyburide. Dig Dis Sci 1996; 41:322.
Report of two patients in whom granulomatous hepatitis developed while they were taking glyburide, and review of the literature on the association.
Scully RE, Galdabini JJ, McNeely BU. Case records of the Massachusetts General Hospital. Case 19-1978. Presentation of a case. Case Records of the Massachusetts General Hospital 1978;298:1133.
Description of a patient with lymphoma who had granulomatous hepatitis.
Stjernberg U, Silseth C, Ritland S. Granulomatous hepatitis in Yersinia enterocolitica infection. Hepatogastroenterology 1987;34:56.
Y. enterocolitica infection was diagnosed by a positive stool culture and serum titer of 1:1280.
Terplan M. Hepatic granulomas of unknown cause presenting with fever. Am J Gastroenterol 1971;55:43.
Sarcoidosis and tuberculosis were the most frequent causes of hepatic granulomas. A characteristic syndrome appears to accompany nonspecific granuloma.
Thung SN, et al. Granulomatous hepatitis in Q fever. Mt Sinai J Med 1986;53:283.
Report of Q fever as a cause of granulomatous hepatitis.
Toft E, Vyberg M, Therkelsen K. Diltiazem-induced granulomatous hepatitis. Histopathology 1991;18:474.
Case report of diltiazem causing granulomatous hepatitis.
Tucker LE. Tocainide-induced granulomatous hepatitis [Letter]. JAMA 1986;27:255.
Tocainide can be added to the list of cardiac drugs reported to cause granulomatous hepatitis.
Zoutman DE, Ralph ED, Frei JV. Granulomatous hepatitis and fever of unknown origin. An 11-year experience of 23 cases with 3 years’ follow-up. J Clin Gastroenterol 1991;13:69.
Specific diagnosis was made in only 26% of patients with fever of unknown origin and granulomatous hepatitis. Forty-one percent had idiopathic disease. These patients had a benign course, although some required long-term steroid therapy.